H3K27me3 and EZH2 expression in melanoma: relevance for melanoma progression and response to immune checkpoint blockade

Hoffmann, Friederike; Niebel, Dennis; Aymans, Pia; Ferring-Schmitt, Sandra; Dietrich, Dimo; Landsberg, Jennifer

doi:10.1186/s13148-020-0818-7

Cited by 37 publications

(27 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our data supports that proteomic profiling of histone methylation levels improves outcome prediction in AML and Ph+ ALL and suggest potential targets to further investigate diagnostically and therapeutically. H3K27me3 loss associates with tumor aggressiveness and patient outcomes in numerous cancers [ 10 – 16 ], similar as we found in AML.…”

Section: Resultssupporting

confidence: 84%

“…Epigenetic dysregulation by histone protein modifications is also well-recognized to play a role in tumor development. Loss of the repressive mark H3K27me3 has been reported in breast, colon, ovarian, pancreatic, prostate, nervous system tumors and melanoma [ 10 – 16 ]. H3K4 di- and trimethylation are associated with open and active chromatin and are predictive factors for outcome in different cancers with low expression of H3K4me2 being associated with poor outcome in prostate, kidney and lung cancer and high expression of H3K4me3 in liver and cervical cancer [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Loss of H3K27 methylation identifies poor outcomes in adult-onset acute leukemia

et al. 2021

View full text Add to dashboard Cite

Background Acute leukemia is an epigenetically heterogeneous disease. The intensity of treatment is currently guided by cytogenetic and molecular genetic risk classifications; however these incompletely predict outcomes, requiring additional information for more accurate outcome predictions. We aimed to identify potential prognostic implications of epigenetic modification of histone proteins, with a focus on H3K4 and H3K27 methylation marks in relation to mutations in chromatin, splicing and transcriptional regulators in adult-onset acute lymphoblastic and myeloid leukemia. Results Histone 3 lysine 4 di- and trimethylation (H3K4me2, H3K4me3) and lysine 27 trimethylation (H3K27me3) mark expression was evaluated in 241 acute myeloid leukemia (AML), 114 B-cell acute lymphoblastic leukemia (B-ALL) and 14T-cell ALL (T-ALL) patient samples at time of diagnosis using reverse phase protein array. Expression levels of the marks were significantly lower in AML than in B and T-ALL in both bone marrow and peripheral blood, as well as compared to normal CD34+ cells. In AML, greater loss of H3K27me3 was associated with increased proliferative potential and shorter overall survival in the whole patient population, as well as in subsets with DNA methylation mutations. To study the prognostic impact of H3K27me3 in the context of cytogenetic aberrations and mutations, multivariate analysis was performed and identified lower H3K27me3 level as an independent unfavorable prognostic factor in all, as well as in TP53 mutated patients. AML with decreased H3K27me3 demonstrated an upregulated anti-apoptotic phenotype. In ALL, the relative quantity of histone methylation expression correlated with response to tyrosine kinase inhibitor in patients who carried the Philadelphia cytogenetic aberration and prior smoking behavior. Conclusion This study shows that proteomic profiling of epigenetic modifications has clinical implications in acute leukemia and supports the idea that epigenetic patterns contribute to a more accurate picture of the leukemic state that complements cytogenetic and molecular genetic subgrouping. A combination of these variables may offer more accurate outcome prediction and we suggest that histone methylation mark measurement at time of diagnosis might be a suitable method to improve patient outcome prediction and subsequent treatment intensity stratification in selected subgroups.

show abstract

Section: Resultssupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Loss of H3K27 methylation identifies poor outcomes in adult-onset acute leukemia

et al. 2021

View full text Add to dashboard Cite

show abstract

“…The co-operative binding of PRC1 (including the BMI1 subunit) and the long noncoding RNA ANRIL to H3K27me3 compacts the CDKN2A genomic locus and represses transcription [ 25 , 30 , 31 , 32 ], in particular the transcription of p16 INK4a [ 33 ]. In line with these data, the levels of H3K27me3 increase from primary to metastatic melanoma, and high H3K27me3 is an independent poor prognostic marker in melanoma [ 34 , 35 ].…”

Section: Somatic Cdkn2a Alterations In Melanomamentioning

confidence: 78%

Genetic Alterations in the INK4a/ARF Locus: Effects on Melanoma Development and Progression

2020

View full text Add to dashboard Cite

Genetic alterations in the INK4a/ARF (or CDKN2A) locus have been reported in many cancer types, including melanoma; head and neck squamous cell carcinomas; lung, breast, and pancreatic cancers. In melanoma, loss of function CDKN2A alterations have been identified in approximately 50% of primary melanomas, in over 75% of metastatic melanomas, and in the germline of 40% of families with a predisposition to cutaneous melanoma. The CDKN2A locus encodes two critical tumor suppressor proteins, the cyclin-dependent kinase inhibitor p16INK4a and the p53 regulator p14ARF. The majority of CDKN2A alterations in melanoma selectively target p16INK4a or affect the coding sequence of both p16INK4a and p14ARF. There is also a subset of less common somatic and germline INK4a/ARF alterations that affect p14ARF, while not altering the syntenic p16INK4a coding regions. In this review, we describe the frequency and types of somatic alterations affecting the CDKN2A locus in melanoma and germline CDKN2A alterations in familial melanoma, and their functional consequences in melanoma development. We discuss the clinical implications of CDKN2A inactivating alterations and their influence on treatment response and resistance.

show abstract

“…The polycomb repressor complex 2 (PRC2) core component molecule EZH2 has been reported to be important in biological processes, such as the cell cycle, cell differentiation, and carcinoma progression [40,41]. Previous studies showed that EZH2 was significantly increased in NB and negatively associated with NB prognosis [42].…”

Section: Discussionmentioning

confidence: 99%

Downregulation of MEG3 promotes neuroblastoma development through FOXO1-mediated autophagy and mTOR-mediated epithelial-mesenchymal transition

Ye¹,

Lü²,

Tang³

et al. 2020

Int. J. Biol. Sci.

View full text Add to dashboard Cite

Our previous studies demonstrated that MEG3 was significantly downregulated in neuroblastoma (NB) and its expression was negatively associated with the INSS stage. Overexpression of MEG3 promoted apoptosis and inhibited proliferation in NB cells. In this study, we discovered more potential functions and molecular mechanisms of MEG3 in NB. According to the database, MEG3 positively correlated with the NB survival rate and was negatively associated with malignant clinical features. Moreover, we determined that MEG3 was mainly located in the nucleus by nuclear-cytoplasmic separation and RNA fish assays. Upregulation of MEG3 in stably transfected cell lines was accomplished, and CCK8, colony formation, and EDU assays were performed, which indicated that MEG3 significantly suppressed cell proliferation. Both wound healing and transwell experiments demonstrated that MEG3 decreased cell migration and invasion. CHIRP enrichments showed the anticancer effects of MEG3 were probably linked to autophagy and the mTOR signaling pathway. LC3 fluorescence dots and western blots showed that MEG3 attenuated autophagy by inhibiting FOXO1, but not the mTOR signaling pathway. Furthermore, MEG3 inhibited metastasis through epithelial-mesenchymal transition via the mTOR signaling pathway. Consistent with the above results, downregulation of MEG3 facilitated NB malignant phenotypes. Mechanistically, MEG3 and EZH2 regulated each other via a negative feedback loop and promoted NB progression together. In conclusion, our findings suggested that MEG3 was a tumor suppressor in NB and could be a potential target for NB treatment in the future.

show abstract

H3K27me3 and EZH2 expression in melanoma: relevance for melanoma progression and response to immune checkpoint blockade

Cited by 37 publications

References 21 publications

Loss of H3K27 methylation identifies poor outcomes in adult-onset acute leukemia

Loss of H3K27 methylation identifies poor outcomes in adult-onset acute leukemia

Genetic Alterations in the INK4a/ARF Locus: Effects on Melanoma Development and Progression

Downregulation of MEG3 promotes neuroblastoma development through FOXO1-mediated autophagy and mTOR-mediated epithelial-mesenchymal transition

Contact Info

Product

Resources

About